Tumor Growth Regulation

Tumorigenesis and cancer progression is a multi-step process that comprises four overlapping series of events: initiation, promotion/proliferation, infiltration, and metastasis. The progression through these steps requires the accumulation of multiple genomic mutations that initiate and sustain the physiological processes that underlie neoplastic cell transformation and survival.

Initiation requires at least two mutations to transformation a normal cell into a cancerous cell – one mutation must activate an oncogene, and an additional mutation must inhibit the activity of a tumor suppressor gene. Research has shown that for human cells to grow as tumors in immune compromised mice, there must be at least five genomic mutations: (1) The Ras (proto-oncogene) pathway must be activated, (2) The pRb cell cycle check point must be inactivated so that mitosis can proceed unchecked, (3) The p53 apoptosis (tumor suppressor) pathway must be inactivated, (4) Telomere maintenance must be activated for cell immortalization, and (5) The protein phosphatase PP2A pathway must be deregulated.

Tumor promoters, such as the phorbol esters, are nonmutagenic factors that stimulate cellular proliferation and cancer. The increased rate of cell division reduces the ability of the cell to repair DNA damage induced by environmental and intracellular mutagens. Mutations that are not fatal to the cell will be replicated in the daughter cells. This process enables the clonal expansion of mutated cells, enhancing the ability of multiple mutations to accumulate. Tumor regulators use a variety of mechanisms of action. Growth factors such as EGF activate receptor tyrosine kinases that activate Ras-induced mitogenic activity. Steroid hormones are mitogenic to cells bearing steroid hormone receptors, such as breast, prostate, and testicular cells. Phorbol esters activate protein kinase Ca, that in turn trigger phosphorylation pathways leading to the catalysis of nuclear transcription factors that support cell immortalization and proliferation.